Pertuzumab Data Highlight Potential of Triplet Regimens in MBC

TITLE

Treating Advanced Breast Cancer in Community Settings

MODERATOR

Adam M. Brufsky, MD, PhD

Professor, Medicine

University of Pittsburgh

Associate Division Chief, Hematology/Oncology

Co-Director, Comprehensive Breast Cancer Center

Pittsburgh, PA

PANELISTS

Sara A. Hurvitz, MD

Associate Professor, Medicine

Ronald Reagan UCLA Medical Center

UCLA Health

Los Angeles, CA

Eleftherios P. Mamounas, MD

Professor, Surgery

University of Florida Health Cancer Center

Orlando, FL

Hope S. Rugo, MD

Professor, Medicine

Breast Director, Breast Oncology Clinical Trials Education

University of California, San Francisco

Helen Diller Family Comprehensive Cancer Center

San Francisco, CA

Dia Voudouris, MD

Clinical Associate Professor, Medicine

Manhattan Cancer Specialists

Mount Sinai School of Medicine

Lenox Hill Hospital

New York, NY

New therapeutic strategies utilizing triplet regimens for the treatment of patients with HER2-positive metastatic breast cancer (MBC) continue to emerge as an exciting area of development, according to a panel of experts who participated in a recent OncLive Peer Exchange.^®

Fresh clinical trial findings have bolstered the role of pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy as a first-line standard of care for this patient population,¹ yet clinicians already were widely employing this regimen based on earlier data.²

Meanwhile, the combination of pertuzumab with trastuzumab and hormonal therapy has generated excitement as a potential option for patients with HER2-positive and estrogen receptor (ER)—positive breast cancer, and represents an area for future research, the panelists said during a wide-ranging discussion entitled “Treating Advanced Breast Cancer in Community Settings.”

CLEOPATRA Solidifies Pertuzumab Regimen

Adam M. Brufsky, MD, PhD, who served as moderator of the Peer Exchange program, called the development of pertuzumab in both early and metastatic disease “one of the big success stories in the treatment of breast cancer” in the past 20 years.

The FDA initially approved pertuzumab in combination with trastuzumab and docetaxel as a frontline treatment for patients with HER2-positive tumors in 2012, based on findings from the phase III CLEOPATRA trial. This indication was followed by the approval of pertuzumab, trastuzumab, and chemotherapy as a neoadjuvant therapy for early-stage HER2-positive breast cancer in 2013.

Adam Brufsky, MD

In September, long-term follow-up results from the CLEOPATRA trial were among the big stories to emerge from the 2014 ESMO Congress in Madrid, Spain. Swain et al reported that dual anti-HER2 blockade with pertuzumab and trastuzumab plus chemotherapy improved median overall survival (OS) by 15.7 months over standard first-line therapy.¹

The triplet combination extended median OS to 56.5 months without introducing any new safety concerns. The data were from the final OS analysis after a median follow-up of 50 months. Adding pertuzumab to the regimen yielded a hazard ratio of 0.68 (P = .0002) compared with standard first-line treatment.

In the CLEOPATRA trial, 808 women were randomized to receive either first-line trastuzumab, docetaxel, and pertuzumab (n = 402) or trastuzumab, docetaxel, and placebo (n = 406). The primary endpoint was progression-free survival (PFS), with secondary outcome measures focused on OS and response.

Patients received either placebo or pertuzumab, given as an 840-mg loading dose followed by a 420-mg maintenance dose, plus trastuzumab, given as an 8-mg/kg loading dose followed by a 6-mg/kg maintenance dose, and 6 cycles of docetaxel, 75 mg/m² with escalation to 100 mg/m² if tolerated. Treatments were administered every 3 weeks and continued until disease progression.

In the primary analysis, the median PFS was 18.5 months versus 12.4 months in the pertuzumab and placebo arms, respectively (HR = 0.62; P <.0001).² The objective response rate was 80.2% in the pertuzumab arm compared with 69.3% with placebo. The median duration of response was 20.2 versus 12.5 months, for the pertuzumab and placebo arms, respectively.

Based on those results, the regimen was frequently used in clinical practice before the long-term data were known, the panelists indicated during the discussion, which was filmed before the ESMO conference.

“You can’t argue with the response rate or with the progression-free survival,” said Sara A. Hurvitz, MD. “I think that’s just incredibly impressive, and so you would want to give your patient that opportunity.”

Dia Voudouris, MD, said the regimen has been working out well for patients in her community-based practice. “We really have found it’s been a very tolerable, very easy to give regimen and patients have done very well,” she said.

Brufsky asked Voudouris whether she substitutes paclitaxel for the chemotherapy piece of the regimen. “We don’t,” Voudouris replied. “We’re community oncologists and we try to stay on-label. Since the trials were done with docetaxel, we do use docetaxel and we found it pretty well tolerated, with less neurotoxicity. Before pertuzumab, we would have used trastuzumab plus docetaxel initially anyway. “

Other questions involving chemotherapy include the duration of treatment. "I’ve seen a lot of questions about how long do we continue the chemo," said Hurvitz. "The CLEOPATRA study did six cycles and then allowed patients to stop the chemotherapy, and that’s what I do routinely in my practice."

PERTAIN Trial Explores Another Triplet

During the discussion, panelists noted that several questions exist regarding the standard of care for patients with HER2-positive and ER-positive MBC, particularly involving the addition of hormonal therapy to chemotherapy or targeted therapy.

"I do incorporate endocrine therapy in patients who co-express the hormone receptors, even though CLEOPATRA did not do that. But I think it makes biological sense," said Hurvitz.

Hope S. Rugo, MD, said there are clinical trial data to support the addition of hormonal therapy to chemotherapy. For one patient, Rugo said she added pertuzumab to hormone therapy and trastuzumab with good results. The woman has receiving the regimen for 2 years, although the insurance company has now withdrawn approval for pertuzumab because the patient no longer has evidence of disease.

"The CLEOPATRA trial continued both antibodies until progression, and that’s where we’re seeing this survival benefit and adding in the hormone therapy is a great thing," said Rugo. "We all have these patients who have been on that regimen for 10 years instead of dying of their cancer. It seems like a better option."

A collection of studies has suggested that HER2 inhibitors work synergistically with hormonal agents. It has been hypothesized that this synergy is the result of MED1 inhibition, a key pathway that connects ER and HER2.

The combination of trastuzumab and fulvestrant was compared with fulvestrant alone in patients with ER-positive and HER2-positive metastatic breast cancer. According to an analysis presented at the 2014 Breast Cancer Symposium, the combination of trastuzumab and fulvestrant resulted in a dramatic prolongation in response.³

In the 85-patient study, 11 patients (13%) were treated with the combination. The median duration of fulvestrant therapy for HER2-positive patients was 772 days, compared with 360 days for HER2-negative patients (P = .059). The odds ratio for patients with HER2-positive breast cancer receiving a longer duration of treatment was 6.2 (P = .0249).

To explore this paradigm further, the phase II PERTAIN study is exploring the combination of pertuzumab, trastuzumab, and an aromatase inhibitor (AI) for postmenopausal women with hormone receptor-positive, HER2-positive MBC.⁴

This study is randomizing patients in a 1:1 ratio to the triplet therapy or trastuzumab plus an AI (either letrozole or anastrozole). Participants may also receive induction chemotherapy of paclitaxel or docetaxel at the investigator’s discretion. The study plans to enroll approximately 250 patients.

"That trial is actually ongoing. It probably will be announced in about a year, 18 months, we’ll figure out,” Brufsky said. “And then hopefully that will be on guidelines and the insurance companies won’t reject it."

HER2 Testing Debate Continues

When it comes to selecting patients for HER2-targeting therapies, the question of how best to evaluate an individual’s HER2 status remains unresolved, even though oncologists have debated the matter for more than a decade.

During the Peer Exchange session, Brufsky posed this question to panelist Eleftherios P. Mamounas, MD: “What is the proper way to test for HER2 in 2014? No one knows the right answer now.”

“I don’t know if I have the right answer,” said Mamounas, whose has explored HER2 testing issues in large clinical trials. “We run into this almost on a daily basis.”

Mamounas said that in adjuvant trials researchers enroll patients with a 3+ immunohistochemistry (IHC) score or with positive in situ hybridization (ISH) scores. Noting that some patients test positive through one method but not the other, Mamounas said, “We’ve seen benefit from both these categories of patients” as well as from patients who did not meet these thresholds.

The lack of clarity about HER2 positivity has prompted the National Surgical Adjuvant Breast and Bowel Project (NSABP) to mount the NSABP B-47 clinical trial,⁵ in which researchers will explore the question of whether patients with a lower threshold of HER2 positivity benefit from trastuzumab, said Mamounas.

NSABP B-47 seeks to recruit 3260 participants with resected node-positive or high-risk, node-negative invasive breast cancer that is HER2-low, defined as an IHC score of 1+ or 2+. If the IHC score is 2+, ISH testing also is required. On ISH testing, the CEP17 ratio must be < 2.0 or, if a ratio was not performed, the HER2 gene copy number must be <4 per nucleus.

Patients will be randomized to receive one of two chemotherapy regimens with or without trastuzumab: (1) docetaxel plus cyclophosphamide, or (2) doxorubicin plus cyclophosphamide followed by weekly paclitaxel.

References

1. Swain S, Kim S, Cortés J. Final overall survival analysis from the CLEOPATRA study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. Presented at: 2014 Congress of the European Society of Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract 350O_PR.
2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer [published online December 7, 2011]. N Engl J Med. 2012;366(2):109-119.
3. Charif M, Lower EE, Kennedy D, et al. The effect of trastuzumab therapy on clinical benefit from fulvestrant treatment for metastatic estrogen receptor-positive breast cancer patients. Presented at: 2014 Breast Cancer Symposium; September 4-6, 2014; San Francisco, CA. Abstract 155.
4. NIH Clinical Trials Registry. www.ClinicalTrials.gov website. Identifier: NCT01491737.
5. NIH Clinical Trials Registry. www.ClinicalTrials.gov website. Identifier: NCT01275677.